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Am J Obstet Gynecol. 2012 November ; 207(5): 405.e1–405.e7. doi:10.1016/j.ajog.2012.07.008.

Use of topiramate in pregnancy and risk of oral clefts

Andrea V Margulis, MD ScD1, Allen A Mitchell, MD2, Suzanne M Gilboa, PhD3, Martha M
Werler, ScD2, Murray A Mittleman, MD DrPH1,4, Robert J Glynn, ScD5, Sonia Hernandez-
Diaz, MD DrPH1, and National Birth Defects Prevention Study
1Department of Epidemiology, Harvard School of Public Health, Boston, MA, US

2Slone Epidemiology Center at Boston University, Boston, MA, US

3NationalCenter on Birth Defects and Developmental Disabilities, Centers for Disease Control
and Prevention, Atlanta, GA, US
4Cardiovascular Epidemiology Research Unit, Beth Israel Deaconess Medical Center, Boston,
MA, US
5Divisionof Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital,
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Boston, MA, US

Abstract
Objective—To evaluate the association between monotherapy topiramate use in pregnancy and
cleft lip with or without cleft palate (CL/P) in the offspring.
Study design—Data from the Slone Epidemiology Center Birth Defects Study (BDS) from
1997–2009 and the National Birth Defects Prevention Study (NBDPS) from 1997–2007 were
analyzed. Conditional logistic regression was used to compare first-trimester use of topiramate
monotherapy to no antiepileptic drug use during the periconceptional period between mothers of
infants with CL/P and mothers of controls for each study separately, and in pooled data.

© 2012 Mosby, Inc. All rights reserved.

Corresponding author, Andrea V Margulis, Harvard School of Public Health, Department of Epidemiology, 677 Huntington Avenue,
Kresge Building, Boston, MA 02115, USA, Tel.: +1 617 792 0861, Fax: +1 617 566 7805, andreamargulis@post.harvard.edu.
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Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
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Potential conflicts of interest
Dr. Margulis reported that the Pharmacoepidemiology program at Harvard School of Public Health, which granted her a student
stipend, receives funds for training grants for students from Pfizer and Asisa. The North American AED Pregnancy Registry, to which
Dr. Hernandez-Diaz devotes less than 5% of her time, received grants from multiple pharmaceutical companies. Dr. Mitchell reported
having Johnson & Johnson stock currently valued at <$20,000. Drs. Mitchell, Werler, Glynn, and Hernandez-Diaz have consulted for
or received grants from pharmaceutical companies whose medications are not the subject of this analysis.
Previous presentations
This manuscript has never been published in whole or in part and is not under revision or in press by other journals. An abstract of an
earlier version has been presented in the 27th International Conference on Pharmacoepidemiology and Risk Management, organized
by the International Society of Pharmacoepidemiology, held in Chicago, IL, on August 15, 2011. These findings were presented at the
US Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee meeting held in Silver Spring, MD,
on February 22, 2012, where the risks and benefits of the topiramate-containing product to treat obesity and related conditions Qnexa
(Vivus Inc., Mountain View, California) were discussed.
Disclaimers
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers
for Disease Control and Prevention.
 Margulis et al. Page 2

Results—BDS contained 785 CL/P cases and 6,986 controls; NBDPS contained 2,283 CL/P
cases and 8,494 controls. The odds ratios (exact 95% confidence intervals) for the association
between topiramate use and CL/P were 10.1 (1.1; 129.2) in BDS, 3.6 (0.7; 20.0) in NBDPS, and
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5.4 (1.5; 20.1) in pooled data.

Conclusions—First-trimester use of topiramate may be associated with CL/P.

Keywords
Antiepileptic drugs; Birth defects; Cleft lip; Oral clefts; Topiramate

INTRODUCTION
Approximately 0.5% of pregnant women in the US have epilepsy. 1 Unless the patient has
been free of seizures for 2–5 years, the current recommendation is to continue antiepileptic
therapy throughout pregnancy to avoid seizures that can cause hypoxic damage to the fetus
and maternal morbidity and mortality. 2 Older antiepileptics, such as phenytoin,
phenobarbital and valproic acid, carry an increased risk for various specific congenital
malformations. 3–5 However, little is known about the fetal safety of the increasingly-used
newer antiepileptics. 6–8

Topiramate was approved in the US for the treatment of generalized tonic-clonic and partial
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seizures in 1996 and for prevention of migraine in 2004 (the prevalence of migraine peaks at
childbearing age in women). 9 In 2006, a generic version was introduced in the US market.
Off-label uses include conditions that are also prevalent among women of reproductive age:
sleep 10,11 and eating disorders, 12 other psychiatric conditions 13,14 and weight loss. 12

Animal studies reported an increased risk of craniofacial defects in litters exposed in utero to
low doses of topiramate, and other malformations and low birth weight at higher doses. 15
Some postmarketing studies in pregnant women have suggested an increased risk in birth
defects overall and, possibly, an increased risk in cleft lip with or without cleft palate (CL/
P); however, evidence is inconclusive because neither the exposure nor oral clefts are
frequent. 7,16–19 The replication of these findings in large case-control studies, using
methods suitable for small sample sizes is critical.

We therefore conducted a matched case-control analysis to evaluate the risk of oral clefts in
infants exposed to topiramate during the first trimester of pregnancy, using data from two
large congenital malformations case-control studies in North America. We report both
study-specific and pooled results.
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MATERIALS AND METHODS

Data sources and study populations
The Boston University Slone Epidemiology Center Birth Defects Study (BDS) and the
Centers for Disease Control and Prevention’s (CDC) National Birth Defects Prevention
Study (NBDPS) share several features related to study design, data collection, case
classification, and analyses, which have been described in detail elsewhere. 20–24 Both
studies include infants with major congenital malformations as cases and infants with no
malformations as controls. Pre-pregnancy and pregnancy exposure information is collected
after delivery by means of a detailed computer-assisted telephone interview conducted in
English or Spanish. Questions focus on maternal medical history and details of medication
use and other exposures from two (BDS) or three (NBDPS) months prior to and through the
end of pregnancy. Specifically, the questionnaires in both studies inquire about the presence

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of seizures or epilepsy and its treatment prior to and during pregnancy. To avoid duplication
of participants, the BDS does not enroll women who are in the same catchments as NBDPS
subjects. BDS subjects included women with conception dates from May 1997 to July 2009
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and the NBDPS included women with expected due dates from October 1997 to December
2007.

During the study period, the BDS recruited mothers of fetuses, stillborn and liveborn infants
with malformations and infants without malformations in the greater metropolitan areas of
Philadelphia, San Diego and Toronto and portions of Massachusetts and New York. Starting
in 1998, subjects also included a random sample of all births without congenital
malformations in Massachusetts as controls. To identify study subjects, BDS staff regularly
review admissions and discharge records of birth centers, community hospitals and pediatric
clinics; subjects are also identified from the birth defects registries in Massachusetts and
New York. Interviews are conducted within 6 months of delivery. 20–22 Infants with
chromosomal abnormalities, single-gene conditions, and malformations associated with
amniotic bands were excluded from the present study. The BDS is HIPAA-compliant and is
approved by the relevant institutional review boards.

To ascertain cases, the NBDPS utilizes the birth defects surveillance systems of Arkansas,
California, Georgia (Metropolitan Atlanta Congenital Defects Program operated by CDC),
Iowa, Massachusetts, North Carolina, New Jersey, New York, Texas and Utah, covering an
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annual birth population of more than 482,000 (approximately 10% of births in the US).
Eligible subjects include liveborn infants with major congenital malformations and with no
accompanying chromosomal abnormalities or single-gene conditions. Most states included
stillborn infants and terminations with major congenital malformations, with the exception
of New Jersey, which did not include either, and Massachusetts, which did not include
terminations. Controls are liveborn infants with no major malformations randomly selected
from birth certificates or hospital discharge data from the participating states. Interviews are
conducted between 6 weeks and 24 months after the estimated date of delivery. 22–24 The
NBDPS is HIPAA-compliant and approved by the institutional review boards of the CDC
and all participating study centers.

Exposure ascertainment
First-trimester exposure was defined as the use of topiramate in the first 90 days after the
conception date (“first trimester”). To avoid confounding by other antiepileptic drugs, the
analysis was restricted to topiramate monotherapy, defined as no use of other antiepileptic
drugs in the first trimester. Information on dose and indication was available in BDS data.

Outcomes
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Both data sources define major congenital malformations as structural malformations with
medical, surgical or cosmetic relevance. In both studies, information on the presence of
congenital malformations is obtained from hospital discharges and medical records and
experts review and classify each identified birth defect. Undescended testis, patent foramen
ovale or patent ductus arteriosus in newborns of less than 37 completed weeks of gestational
age at birth are not included in analyses of either data set. The current study focused on
cases diagnosed with CL/P, as this was the specific malformation hypothesized to be
associated with topiramate in previous postmarketing studies. Because some shared risk
factors have been identified, 25 we also planned to separately consider risks for cleft palate
alone (CP). However, there were no infants with CP exposed to topiramate in either study,
so no further analysis was conducted.

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Statistical analyses
Main analysis—We used conditional logistic regression to compare the use of topiramate
monotherapy in the first trimester to no antiepileptic use in the 60 days prior to conception
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or in the first 90 days of pregnancy. All odds ratios (ORs) are reported with exact 95%
confidence intervals. The analysis focused on major congenital malformations as a group
(including oral clefts) and separately on CL/P with or without other major congenital
malformations. In the study-specific primary analyses, matched sets were formed on the
basis of year (2-year categories) and region (California, Massachusetts, New York,
Pennsylvania, and Ontario for BDS and Arkansas, California, Georgia, Iowa, Massachusetts,
New Jersey, New York, North Carolina, Texas, and Utah for NBDPS) of birth, to account
for potential differences in case selection that might have been introduced across regions and
time. Matched sets contained as many cases and controls as were available per stratum. In
analyses on pooled data, matched sets were formed on the basis of year and region of birth
and study (BDS and NBDPS).

Confounding factors—Given the small number of exposed subjects involved in the

analyses, it would be inappropriate to attempt to control confounding by traditional
multivariable approaches. Instead, in our secondary analyses, to assess potential
confounding by characteristics beyond year and region of birth, we repeated the conditional
logistic regression analysis in the pooled data on new matched sets. To form these sets, we
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matched in this analysis case infants to control infants on year and region of birth, study, and
one more variable at a time from the following a priori defined list: maternal race/ethnicity,
family history of oral clefts (first-degree relatives with CL/P or CP), maternal age at
conception (age less than 25, [25; 30), [30; 35), 35 years and over), prepregnancy maternal
body mass index (BMI; less than 18.5 kg/m2, [18.5; 25), [25; 30), 30 and over), first-
trimester cigarette smoking, first-trimester alcohol consumption, diagnosis of epilepsy,
diagnosis of diabetes or gestational diabetes prior to or during the index pregnancy, and folic
acid supplementation from single-ingredient or folic-acid containing multivitamin products
(any use in the 2 months prior to the beginning of pregnancy or the first 2 months of
pregnancy).

Dose and indication—We identified daily dose and indication among infants with CL/P
and among controls from BDS.

Analyses were performed in SAS 9.1 (SAS Institute Inc., Cary, NC, USA).

RESULTS
Slone Birth Defects Study
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The study population consisted of 6,983 controls and 10,618 infants with major congenital
malformations (the latter excluded 2,594 infants with chromosomal abnormalities, single-
gene inherited diseases, malformations associated with amniotic bands, syndromic or
metabolic disorders). Among the infants with malformations, 785 had CL/P. Maternal and
offspring characteristics of CL/P cases and controls are presented in Table 1. Five infants
with malformations were exposed to topiramate monotherapy, of which 3 had CL/P; 2 of the
controls were exposed to topiramate. The OR comparing first-trimester exposure to
topiramate monotherapy to no antiepileptic drug use for major congenital malformations
was 1.22 (0.19; 13.01) and for CL/P was 10.13 (1.09; 129.21) (Table 2).

The daily dose and indication of topiramate among cases of CL/P were 25 mg (migraine)
and 100 mg (epilepsy); the third case mother, who took the drug for depression, did not

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 Margulis et al. Page 5

report dose. The 2 control infants were both exposed to a daily dose of 100 mg for migraine
prophylaxis.
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National Birth Defects Prevention Study

The study population consisted of 8,494 controls and 23,333 case infants. Of them, 2,283
had CL/P. Maternal and offspring characteristics of CL/P cases and controls are presented in
Table 1. Ten case infants, including 4 infants with CL/P, and 4 control infants received first-
trimester monotherapy exposure to topiramate. The OR comparing first-trimester exposure
to topiramate and no antiepileptic drug use for major congenital malformations was 0.92
(0.26; 4.06) and for CL/P was 3.63 (0.66; 20.00). The mothers of 2 infants with major
congenital malformations (1 of them with CL/P) and of 1 control infant reported having
been diagnosed with epilepsy.

Pooled data
Among the pooled study population, first-trimester monotherapy exposure to topiramate was
not associated with an increase in the risk of major congenital malformations overall (OR
1.01 [0.37; 3.22]), but it was associated with an elevated risk of CL/P (OR 5.36 [1.49;
20.07)]. Point estimates and confidence intervals were not substantially modified by
matching on any additional characteristic in the analyses of either major congenital
malformation (OR point estimates varied between 0.91 and 1.03) or CL/P (OR point
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estimates varied between 4.01 and 5.92) (data not shown).

COMMENT
Monotherapy topiramate use during the first trimester of pregnancy was associated with an
increased risk of CL/P as compared to no use of antiepileptics in pooled data from BDS and
NBDPS.

Topiramate has effects on multiple physiologic pathways. It affects cell polarization through
effects on various ion channels; it also inhibits the carbonic anhydrase 12,26 and histone
deacetylases; histone deacetylases are also inhibited by valproic acid. 27 Litters born to
pregnant rodents exposed to doses equivalent to 50% of the recommended human dose for
epilepsy, or below, had an increased incidence of craniofacial defects (mice), low birth
weight (mice and rats) or other structural variations (rats). 15 Rabbits were only affected at
high doses.

In humans, a number of results, each based on a small number of exposed subjects,

collectively suggest that the risk of major malformations is not increased or not largely so,
but that the risk of CL/P may be elevated. Our findings support these results. In 2008, Hunt
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et al. reported an incidence of CL/P 11 times the background rate for topiramate-exposed
infants in monotherapy, based on 2 cases among 70 exposures from the UK Epilepsy and
Pregnancy Register; there were 3 infants with major congenital malformations in total.18 In
the same year, Ornoy et al. reported 1 infant with a major congenital malformation (not an
oral cleft) among 29 women exposed to topiramate monotherapy using the Israeli
Teratology Service data.17 In 2010, Hernández-Díaz et al. reported in an abstract 4 cases of
cleft lip in 289 infants exposed in monotherapy in the first trimester in the North American
Antiepileptic Drug Pregnancy Registry, which represented an elevated risk compared to an
external reference population. 19 These results were used by the U.S. Food and Drug
Administration in March 2011, to reclassify topiramate from pregnancy category C to
pregnancy category D. 28 Further information has been presented subsequent to these
reports. In a population-based Danish cohort focused on newer antiepileptic medications,
Molgaard-Nielsen et al. identified 108 first-trimester topiramate-exposed pregnancies,

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among which there were 5 born with malformations; while they reported no significant
increase in overall risk (OR = 1.44), it is of interest that one of the malformed infants had a
CL/P (an absolute risk of 1% with wide confidence intervals). 7 Additional reports, available
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only as abstracts, include a study by Day et al. 29 that reported almost identical risks of
major congenital malformations in infants with topiramate monotherapy exposure in utero
and infants born from untreated epileptic women, using pooled data from a variety of
international sources, overlapping with some of the above (relative risk = 1.03). Pack et al.30
reported no association between topiramate use in the 10 months prior to delivery and either
major congenital malformations or oral clefts, relative to users of other antiepileptic drugs
(relative risk for major congenital malformations = 1.18; for oral clefts, 1.26) and women
with epilepsy who were not receiving topiramate (relative risk for major congenital
malformations = 0.87; for oral clefts, 0.85), using commercial claims data from the US.

To our knowledge, no other specific malformations have been associated with topiramate.
While our findings do not suggest that topiramate increases the risk of malformations
overall, we considered only one hypothesis related to specific malformations—CL/P.
Although we observed no increased risk for other major malformations as a group, we
cannot exclude the possibility that topiramate may be related to a modest increase in one or
more specific defects.

Though we were unable to perform a full dose-response analysis, our limited results do not
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suggest a threshold effect on infants born with CL/P, since one case was exposed to the low
dose of 25 mg/d for migraine prevention.

Several antiepileptic drugs (e.g., valproic acid, carbamazepine, phenytoin, phenobarbital,

lamotrigine) have been associated with an increased risk of specific congenital
malformations (e.g., oral clefts, neural tube defects, heart defects, hypospadias,
craniosynostosis, polydactyly). 4,5,31–33 A dose-related risk for major congenital
malformations overall has been reported for valproic acid, phenobarbital, lamotrigine and
carbamazepine, 34,35 though consistently replicated only for valproic acid.36,37 There is
disagreement on whether antiepileptic drugs or epilepsy itself are responsible for the
congenital malformations found in the infants born to epileptic women who are on
antiepileptic treatment. Studies reported that epileptic women who do not use antiepileptic
drugs during pregnancy are not at a higher risk of delivering affected infants than non-
epileptic women who were not exposed to antiepileptic medications. 3,5,38 However,
residual confounding by epilepsy severity is generally difficult to rule out, as severe, active
epilepsy rarely remains untreated. In this study, epilepsy was reported by less than half of
topiramate users. Epilepsy was a weak confounder; we could not assess the impact of
seizures in pregnancy on congenital malformations. To our knowledge, no reports have
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suggested an association between migraine and congenital malformations. The vasoactive

drug ergotamine, used to treat migraine crises, is contraindicated in pregnancy because of its
risk of fetopathy, 39 but none of the women exposed to topiramate in our study reported
exposure to ergotamine.

Despite our use of data from two large birth defects case-control studies, the main limitation
of this analysis is its low number of exposed cases and exposed controls. For this reason,
even though we applied methods that are appropriate for small cell counts, our ability to
control for confounding is limited. We matched on data collection-related factors in all
analyses and assessed other potential confounders individually, but we could not assess
confounding by combinations of these or conduct stratified analyses due to the paucity of
data. The differences in effect size for topiramate and CL/P between the BDS and NBDPS
may be due to sampling variability, different amounts of residual confounding or varying
underlying risk.

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Our results must be interpreted in light of several additional limitations: recall bias is a
potential limitation of this study, as exposure information is collected after the pregnancy
outcome is known. To diminish the potential for bias, the computer-assisted interview is
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scripted, ensuring identical questions are asked to mothers of case and control infants. Recall
is enhanced by presenting the interviewees with a list of medications and illnesses in the
script. Some studies have attempted to diminish the risk of recall bias by comparing infants
with the malformation of interest to infants with malformations unrelated to the exposure. In
this study, we did not use such a comparison group because the safety pattern of topiramate
is not yet well characterized. However, the fact that we found an association with only the a
priori hypothesized malformation (i.e., CL/P) and not with overall malformations argues
against recall bias.

Pregnancies terminated because of congenital malformations in the fetus are eligible for
inclusion in BDS and in most of the participating states in NBDPS. Neither data source
identifies the presence of congenital malformations in spontaneous abortions less than 20
gestational weeks. This potential underascertainment of major congenital malformations
would bias risk estimates towards the null. However, CL/P is not lethal and we do not
expect substantial underascertainment of CL/P in the absence of associated syndromes or
chromosomal abnormalities.

In conclusion, the results of our pooled analysis are consistent with recent reports of an
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increased risk of CL/P associated with the use of topiramate in the first trimester of
pregnancy. However, the absolute risk should be kept in perspective. Approximately 1 in
1,000 infants is born with CL/P; 40,41 assuming our results are valid and accurate, our
observed pooled OR of approximately 5 would translate into a risk in the order of 5/1,000
for any individual topiramate-exposed pregnancy. Clinical decision-makers should weigh
the risks of treatment with topiramate against the risks of alternative therapeutic choices, as
well as the comparative effectiveness of topiramate and alternative treatments.

Acknowledgments
Coding of drug information in the NBDPS used the Slone Drug Dictionary under license from the Slone
Epidemiology Center at Boston University.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official
position of the Centers for Disease Control and Prevention.

We thank the health care providers, project coordinators, medical records reviewers, interviewers, research
assistants, programmers in all study centers and participating institutions, and the mothers who were interviewed
for the studies.
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Financial support

The sources of funding for this study were: cooperative agreement no. U50/CCU113247 with the Centers for
Disease Control and Prevention to the SEC through the Massachusetts Department of Public Health; cooperative
agreements under PA 96043, PA 02081 and FOA DD09-001 from the Centers for Disease Control and Prevention
to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention
Study; and Grant RO1 HD 046595 from the Eunice Kennedy Shriver National Institute of Child Health and Human
Development.

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Table 1
Maternal and offspring characteristics of study participants, Slone Birth Defects Study (1997–2009) and
NIH-PA Author Manuscript

National Birth Defects Prevention Study (1997–2007).

Slone Birth Defects Study National Birth Defects Prevention

Study

Characteristics Infants without Infants with Infants Infants with CL/P

malformations CL/P without N = 2,283
N = 6,983 N = 785 malformations
N = 8,494

Maternal age in years, mean (SD) 29.3 (5.9) 28.5 (6.1) 27.3 (6.1) 27.0 (6.1)
Prepregnancy BMI in kg/m2, N (%)
Less than 18.5 207 (3.0) 38 (4.8) 439 (5.2) 150 (6.6)
[18.5; 25) 3,964 (56.8) 379 (48.3) 4,180 (49.2) 1,069 (46.8)
[25; 30) 1,564 (22.4) 173 (22.0) 2,033 (23.9) 504 (22.1)
[30; 35) 566 (8.1) 75 (9.6) 912 (10.7) 255 (11.2)
35 and over 327 (4.7) 52 (6.6) 564 (6.6) 182 (8.0)
Maternal race/ethnicity, N (%)
Non-Hispanic White 4,917 (70.4) 507 (64.6) 5,004 (58.9) 1,376 (60.3)
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Non-Hispanic Black 538 (7.7) 65 (8.3) 959 (11.3) 139 (6.1)

Hispanic 997 (14.3) 124 (15.8) 1,975 (23.3) 609 (26.7)
Asian/Pacific Islander 386 (5.5) 71 (9.0) 250 (2.9) 59 (2.6)
Native American/Alaskan Native NA NA 43 (0.5) 19 (0.8)
Other 139 (2.0) 15 (1.9) 260 (3.1) 81 (3.5)
Maternal education in years, N (%)
Less than or 13 1,936 (27.7) 287 (36.6) 3,446 (40.6) 1,106 (48.4)
[13; 15] 1,635 (23.4) 195 (24.8) 2,260 (26.6) 583 (25.5)
16 and over 3,409 (48.8) 303 (38.6) 2,637 (31.0) 573 (25.1)
First-degree relative with CL/P or CP 31 (0.4) 56 (7.1) 29 (0.3) 126 (5.5)
Diabetes, N (%) 365 (5.2) 67 (8.5) 559 (6.6) 204 (8.9)
Periconceptional folic acid supplementation, N (%) 6,087 (87.2) 640 (81.5) 6,282 (74.0) 1,654 (72.4)
Any smoking in first trimester, N (%) 1,150 (16.5) 174 (22.2) 1,350 (15.9) 494 (21.6)
Any alcohol use in first trimester, N (%) 2,754 (39.4) 257 (32.7) 3,087 (36.3) 850 (37.2)

CL/P: cleft lip with or without cleft palate – CP: cleft palate – BMI: body mass index – NA: category not available
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Note: Missing data among non-malformed infants and infants with CL/P: Slone Birth Defects Study: 423 subjects did not report their BMI, 9
subjects did not report race/ethnicity, 3 did not report years of education, 262 did not report on smoking status and 37 did not report on alcohol
intake; National Birth Defects Prevention Study: 489 subjects did not report their BMI, 3 subjects did not report race/ethnicity, 172 did not report
years of education, 144 did not report on smoking status.

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Table 2
Use of topiramate in monotherapy in the first trimester of pregnancy and risk of major congenital malformations and CL/P, Slone Birth Defects Study
(1997–2009) and National Birth Defects Prevention Study (1997–2007).

Use of antiepileptic drugs Infants Infants with major Infants with CL/P
Margulis et al.

without congenital
malformations malformations a
N N OR (95% CI) N OR (95% CI)

Slone Birth Defects Study b

No use of antiepileptic drugs c 6,933 10,503 Reference 778 Reference

Topiramate monotherapy in first trimester 2 5 1.22 (0.19 – 13.01) 3 10.13 (1.09 – 129.21)

National Birth Defects Prevention Study b

No use of antiepileptic drugs 8,434 23,102 Reference 2,256 Reference

Topiramate monotherapy in first trimester 4 10 0.92 (0.26 – 4.06) 4 3.63 (0.66 – 20.00)

Pooled data d

No use of antiepileptic drugs 15,367 33,605 Reference 3,034 Reference

Topiramate monotherapy in first trimester 6 15 1.01 (0.37 – 3.22) 7 5.36 (1.49 – 20.07)

CL/P: cleft lip with or without cleft palate – OR: odds ratio – 95%CI: 95% confidence interval
a
The major congenital malformations found in topiramate-exposed infants were left cleft lip, right cleft lip and cleft palate, unilateral cleft lip and palate (unspecified side), cleft lip (not otherwise specified),
bilateral cleft lip, bilateral cleft lip and palate, left Bochdalek diaphragmatic hernia, patent ductus arteriosus, patent foramen ovale, atrial septal defect (ostium secundum type), unspecified atrial septal
defect, unspecified ventricular septal defect, coarctation of the aorta, pulmonary valve stenosis, unspecified brain anomalies, spina bifida, and anal atresia with fistula.
b
Analyses conditional on year and region of birth.

Am J Obstet Gynecol. Author manuscript; available in PMC 2013 November 01.

c
No AED use refers to no use of antiepileptic drugs in the 2 months prior to pregnancy or in the first trimester of pregnancy
d
Analyses conditional on year and region of birth, and study.
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